SARS-CoV-2 and HCoV-OC43 Regulate Host M6A Modification Via Activation of the MTORC1 Signalling Pathway to Facilitate Viral Replication

Overview

Journal Emerg Microbes Infect

Specialty Infectious Diseases

Date 2025 Jan 2

PMID 39745173

Authors

Shixiong Zhou

Xianfeng Hui

Weiwei Wang

Chunbei Zhao

Meilin Jin

Yali Qin

Mingzhou Chen

Affiliations

Soon will be listed here.

Abstract

N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification in eukaryotic RNA and is also present in various viral RNAs, where it plays a crucial role in regulating the viral life cycle. However, the molecular mechanisms through which viruses regulate host RNA m6A methylation are not fully understood. In this study, we reveal that SARS-CoV-2 and HCoV-OC43 infection enhance host m6A modification by activating the mTORC1 signalling pathway. Specifically, the viral non-structural protein nsp14 upregulates the expression of S-adenosylmethionine synthase MAT2A in an mTORC1-dependent manner. This mTORC1-MAT2A axis subsequently stimulates the synthesis of S-adenosylmethionine (SAM). The increase of SAM then enhances the m6A methylation of host RNA and facilitates viral replication. Our findings uncover a molecular mechanism by which viruses regulate host m6A methylation and provide insights into how SARS-CoV-2 hijacks host cellular epitranscriptomic modifications to promote its replication.

References

Foster K, Acosta-Jaquez H, Romeo Y, Ekim B, Soliman G, Carriere A . Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. J Biol Chem. 2009; 285(1):80-94. PMC: 2804229. DOI: 10.1074/jbc.M109.029637. View

Imprachim N, Yosaatmadja Y, Newman J . Crystal structures and fragment screening of SARS-CoV-2 NSP14 reveal details of exoribonuclease activation and mRNA capping and provide starting points for antiviral drug development. Nucleic Acids Res. 2022; 51(1):475-487. PMC: 9841433. DOI: 10.1093/nar/gkac1207. View

Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G . Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc. 2013; 8(1):176-89. DOI: 10.1038/nprot.2012.148. View

Tan B, Liu H, Zhang S, Ramos da Silva S, Zhang L, Meng J . Viral and cellular N-methyladenosine and N,2'-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat Microbiol. 2017; 3(1):108-120. PMC: 6138870. DOI: 10.1038/s41564-017-0056-8. View

Dennis M, Baum J, Kimball S, Jefferson L . Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids. J Biol Chem. 2011; 286(10):8287-8296. PMC: 3048714. DOI: 10.1074/jbc.M110.209171. View

Villa E, Sahu U, OHara B, Ali E, Helmin K, Asara J . mTORC1 stimulates cell growth through SAM synthesis and mA mRNA-dependent control of protein synthesis. Mol Cell. 2021; 81(10):2076-2093.e9. PMC: 8141029. DOI: 10.1016/j.molcel.2021.03.009. View

Qi F, Zhang W, Huang J, Fu L, Zhao J . Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019. Front Immunol. 2021; 12:651656. PMC: 8079812. DOI: 10.3389/fimmu.2021.651656. View

Zhang Z, Liu Q, Sun Y, Li J, Liu J, Pan R . Live attenuated coronavirus vaccines deficient in N7-Methyltransferase activity induce both humoral and cellular immune responses in mice. Emerg Microbes Infect. 2021; 10(1):1626-1637. PMC: 8381960. DOI: 10.1080/22221751.2021.1964385. View

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

10.

Yang G, Francis D, Krycer J, Larance M, Zhang Z, Novotny C . Dissecting the biology of mTORC1 beyond rapamycin. Sci Signal. 2021; 14(701):eabe0161. PMC: 8580572. DOI: 10.1126/scisignal.abe0161. View

11.

Burgess H, Depledge D, Thompson L, Srinivas K, Grande R, Vink E . Targeting the mA RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication. Genes Dev. 2021; 35(13-14):1005-1019. PMC: 8247602. DOI: 10.1101/gad.348320.121. View

12.

Li T, Kenney A, Park J, Fiches G, Liu H, Zhou D . SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling. Front Immunol. 2022; 13:1007089. PMC: 9513374. DOI: 10.3389/fimmu.2022.1007089. View

13.

Vann K, Tencer A, Kutateladze T . Inhibition of translation and immune responses by the virulence factor Nsp1 of SARS-CoV-2. Signal Transduct Target Ther. 2020; 5(1):234. PMC: 7545794. DOI: 10.1038/s41392-020-00350-0. View

14.

Li G, Hilgenfeld R, Whitley R, De Clercq E . Therapeutic strategies for COVID-19: progress and lessons learned. Nat Rev Drug Discov. 2023; 22(6):449-475. PMC: 10113999. DOI: 10.1038/s41573-023-00672-y. View

15.

Gokhale N, McIntyre A, McFadden M, Roder A, Kennedy E, Gandara J . N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection. Cell Host Microbe. 2016; 20(5):654-665. PMC: 5123813. DOI: 10.1016/j.chom.2016.09.015. View

16.

Meng Y, Zhang Q, Wang K, Zhang X, Yang R, Bi K . RBM15-mediated N6-methyladenosine modification affects COVID-19 severity by regulating the expression of multitarget genes. Cell Death Dis. 2021; 12(8):732. PMC: 8298984. DOI: 10.1038/s41419-021-04012-z. View

17.

Baksh S, Finley L . Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases. Trends Cell Biol. 2020; 31(1):24-36. PMC: 7748998. DOI: 10.1016/j.tcb.2020.09.010. View

18.

Wang X, Zhao B, Roundtree I, Lu Z, Han D, Ma H . N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161(6):1388-99. PMC: 4825696. DOI: 10.1016/j.cell.2015.05.014. View

19.

Purslow J, Nguyen T, Khatiwada B, Singh A, Venditti V . -methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5. Sci Adv. 2021; 7(34). PMC: 8373141. DOI: 10.1126/sciadv.abi8215. View

20.

Hao H, Hao S, Chen H, Chen Z, Zhang Y, Wang J . N6-methyladenosine modification and METTL3 modulate enterovirus 71 replication. Nucleic Acids Res. 2018; 47(1):362-374. PMC: 6326802. DOI: 10.1093/nar/gky1007. View